EP2042174B1 - Klebende zubereitung - Google Patents

Klebende zubereitung Download PDF

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Publication number
EP2042174B1
EP2042174B1 EP07767707.8A EP07767707A EP2042174B1 EP 2042174 B1 EP2042174 B1 EP 2042174B1 EP 07767707 A EP07767707 A EP 07767707A EP 2042174 B1 EP2042174 B1 EP 2042174B1
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EP
European Patent Office
Prior art keywords
patch preparation
drug
polyisobutylene
pressure
sensitive adhesive
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Active
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EP07767707.8A
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English (en)
French (fr)
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EP2042174A4 (de
EP2042174A1 (de
Inventor
Sachiko Honma
Tetsuro Tateishi
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Hisamitsu Pharmaceutical Co Inc
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Hisamitsu Pharmaceutical Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a patch preparation and more particularly, to a patch preparation containing fentanyl and/or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Fentanyl a selective ⁇ -opioid agonist
  • One of the preferred embodiments of the transdermal administration is to use a patch preparation wherein a drug layer (containing a drug and a pressure-sensitive adhesive), formed on a backing layer, is covered with a release liner.
  • a drug layer containing a drug and a pressure-sensitive adhesive
  • a release liner is covered with a release liner.
  • a pressure-sensitive adhesive it is common for a pressure-sensitive adhesive to contain liquid ingredients such as solubilizers, solubilizing adjuvants, transdermal absorption enhancers, and the like.
  • liquid ingredients such as solubilizers, solubilizing adjuvants, transdermal absorption enhancers, and the like.
  • containing such ingredients posed a problem in that the cohesive force of an adhesive base was reduced.
  • the cohesive force of an adhesive base is reduced, the skin permeability of a drug tends to be also reduced.
  • liquid ingredients in a pressure-sensitive adhesive are increased for the purpose of enhancing the diffusion and skin permeation of a drug, it may, on the contrary, deteriorate the skin permeability of the drug.
  • fentanyl have low skin permeability. Due to this property, when fentanyl is contained in a pressure-sensitive adhesive, it is imperative to add a large amount of liquid ingredients in the pressure-sensitive adhesive to attain adequate drug diffusion and skin permeation. However, since a large amount of liquid ingredients added causes reduced cohesive force of an adhesive base due to the reason described above, it raised a problem that sufficient skin permeability of a drug could not be achieved.
  • Patent Documents 1 to 4 fentanyl-containing patch preparations are disclosed in Patent Documents 1 to 4. More specifically, known patch preparations include; patch preparations in reservoir formulation and multilaminate formulation (Patent Document 1), a patch preparation containing an organic acid salt, a styreneisoprene-styrene block copolymer and polyisobutylene (Patent Document 2), a patch preparation containing N-methyl-2-pyrrolidone (Patent Document 3), and a patch preparation in which fentanyl particles are suspended in more than 1 solvated silicone-based pressure-sensitive adhesive (Patent Document 4).
  • WO 2004/098567 discloses transdermal dosage forms comprising an active agent-containing component comprising a polymeric material and an active agent (e.g. fentanyl).
  • the polymeric material can be a pressure-sensitive adhesive such as an acrylate, polyisobutylene, a silicon polymer and mixtures thereof.
  • WO 93/00058 discloses transdermal compositions comprising a drug, an acrylate polymer and a polysiloxane.
  • active drug fentanyl is mentioned.
  • WO 2004/017941 discloses a transdermal dosage form comprising an adhesive matrix having dispersed therethrough an active agent which is supported on a backing layer.
  • an active agent polyisobutylenes and polysiloxanes are mentioned.
  • fentanyl is mentioned.
  • WO 2005/123046 discloses a transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer.
  • the pressure-sensitive adhesive silicon pressure-sensitive adhesives are mentioned, and as a rubber-based pressure-sensitive adhesive, polyisobutylene is mentioned.
  • the active ingredient contained in the matrix layer of the transdermal preparation can be fentanyl.
  • US 2006/078604 describes a transdermal drug delivery system comprising a carrier composition layer incorporating an active agent and a non-drug containing backing layer.
  • the carrier composition may comprise silicon-based polymers or polyisobutylenes.
  • Transdermal drug delivery systems BIOMATERIALS, ELSEVIER SCIENCE PUBLISHERS BV., BARKING, GB, vol. 19, no. 13 , is a review article describing transdermal drug delivery systems. It mentions a fentanyl-containing commercial transdermal delivery system containing a silicon-based contact adhesive.
  • the fentanyl-containing reservoir patch preparation disclosed in Patent Document 1 has a drug reservoir layer in which a drug is enclosed in a solution or semisolid form. For this reason, it requires highly precisional manufacturing processes to prevent the drug from volatilization and leakage. Further, since such a reservoir patch preparation structurally requires a drug release rate-controlling membrane, the number of parts composing a patch preparation increases, etc., thereby posing a problem by complicating the manufacturing process.
  • the fentanyl-containing multilaminate patch preparation disclosed in Patent Document 1 requires to contain a large amount (e.g., 10 to 30%) of fentanyl in a pressure-sensitive adhesive, wherein the fentanyl is likely to be crystallized over time, causing an undesirable problem from the viewpoints of adhesion and drug release.
  • the fentanyl-containing patch preparations disclosed in Patent Documents 2 and 3 require a number of restrictions in conditions of manufacturing processes (pulverizing, mixing, film forming, and drying), complicating the production method which is problematic. Further, the fentanyl-containing patch preparation disclosed in Patent Document 3 had high drug releasability or absorption, thereby causing a problem in that the drug tends to quickly deplete when applied. Furthermore, the fentanyl-containing patch preparation of Patent Document 3 had a problem of the so-called "sticking-out".
  • the patch preparation is typically packaged individually in a water impermeable packaging material to prevent the contained drug from being volatilized or affected by humidity.
  • an individually packaged patch preparation had the so-called "sticking-out" problem, which causes a pressure-sensitive adhesive to protrude from the edge of a patch preparation and stick to the inner surface of the packaging material or a pressure-sensitive adhesive to extend behind the backing layer, making it difficult to take the patch preparation for use.
  • the pressure-sensitive adhesive contains a plasticizer, tackifier, solubilizer, etc.
  • these agents stick out from the edge of the drug layer and attach (extend) to the back of the backing layer or release liner, even to the inner surface of the packaging material. Consequently, the patch preparation adheres to the inner surface of the packaging material, making it difficult to take the patch preparation.
  • the fentanyl-containing patch preparation disclosed in Patent Document 4 posed problems such as low adhesion, poor peeling of the release liner.
  • An object of the present invention is to provide a fentanyl-containing patch preparation that is manufactured easily, prevented sufficiently from the sticking-out and crystal formation, and imparted good drug permeability through the skin.
  • a patch preparation comprising a backing layer and a drug layer laminated on the backing layer, wherein the drug layer consists of a pressure-sensitive adhesive comprising polyisobutylene, a silicon-containing polymer and at least one compound selected from the group consisting of fentanyl and pharmaceutically acceptable salts thereof, and a mass ratio of the polyisobutylene and the silicon-containing polymer in the pressure-sensitive adhesive is 20:1 to 7:3.
  • Such a fentanyl-containing patch preparation is easily manufactured, sufficiently prevented from the sticking-out and crystal formation, and imparted good skin permeability. The reason rendering these effects is yet to be discovered. However, it is presumably at least due to the use of a mixture of polyisobutylene and a silicon-containing polymer as a pressure-sensitive adhesive substance (hereinafter sometimes referred to as "adhesive base") in which fentanyl is to be contained and also set the mass ratio for such a mixture within the specified range.
  • adheresive base a pressure-sensitive adhesive substance
  • the patch preparation having the above structure requires a small number of parts for the manufacture and is less restrictive in manufacturing process conditions, thereby providing an effect that manufacturing process is easier than those for known patch preparations.
  • the conventional fentanyl-containing patch preparations are likely to leave the pressure-sensitive adhesive on the skin (hereinafter referred to as "adhesive remnant") when a patch preparation is detached from the skin, imposing a burden to a patient.
  • adhesive remnant can be sufficiently prevented.
  • the abovementioned polyisobutylene comprises a high molecular weight polyisobutylene having an average molecular weight of 800,000 to 1,600,000 and a low molecular weight polyisobutylene having an average molecular weight of 30,000 to 80,000.
  • the adhesion of the patch preparation can be hence improved.
  • the silicon-containing polymer described above be a polymer having an organopolysiloxane skeleton (preferably an organopolysiloxane skeleton) or a composition containing such a polymer.
  • Preferred polymers having an organopolysiloxane skeleton have hydroxyl groups thereof at least partially capped by a trimethylsilyl group.
  • the polymer having an organopolysiloxane skeleton wherein at least a part of its hydroxyl group is capped by a trimethylsilyl group has a small number of free silanol groups, and hence has a low interaction with a drug (e.g., chemical and physical bond), whereby the drug releasability tends to increase.
  • the silicon-containing polymer may be a composition containing a polymer having an organopolysiloxane skeleton, it is preferable for the composition to be a pressure-sensitive composition.
  • a composition does not deteriorate the adhesion of an adhesive constituting a drug layer and maintains good releasability of fentanyl or a pharmaceutically acceptable salt thereof.
  • the pressure-sensitive adhesive preferably contains a transdermal absorption enhancer.
  • a transdermal absorption enhancer enables effective drug absorption to the skin.
  • the above transdermal absorption enhancer is preferably at least one compound selected from the group consisting of isopropyl myristate, isopropyl palmitate, sorbitan monooleate, oleyl alcohol, propylene glycol, dipropylene glycol, octyl dodecanol.
  • the use of such an enhancer enables the drug skin permeability to be further improved.
  • the area of the drug layer to be contacted with the skin is preferably 5 to 50 cm 2 .
  • the fentanyl-containing patch preparation which is easily manufactured, sufficiently prevented from the sticking-out and crystal formation, and has good skin permeability, adhesion and tackiness to the skin, is provided. Further, according to the present fentanyl-containing patch preparation, the adhesive remnant is adequately prevented and the drug is absorbed for a longer time than the conventional fentanyl-containing patch preparations, thereby relieving the burden of patients.
  • Figure 1 is a graph showing changes over time in the drug permeability when the patch preparation of the present invention is applied to the skin.
  • the patch preparation according to the present invention comprises a backing layer and a drug layer where drug layer consists of a specific adhesive and is laminated on the backing layer.
  • the pressure-sensitive adhesive comprises a drug having at least one activity (drug potency) selected from the group consisting of fentanyl and pharmaceutically acceptable salts thereof, and an adhesive base comprising polyisobutylene and a silicon-containing polymer.
  • the pressure-sensitive adhesive may contain, as an active drug, fentanyl and a pharmaceutically acceptable salt thereof independently or together as a mixture. However, it is preferable to contain fentanyl singly because an active drug has to be contained in the pressure-sensitive adhesive in a dissolved state.
  • the fentanyl content in the drug layer is preferably 1 to 6% based on the whole mass of the drug layer.
  • a fentanyl content of 1% or more easily enables the patch preparation to deliver a sufficient drug permeation through the skin, and a fentanyl content of 6% or less can definitely eliminate adverse influence to the physical properties of the patch preparation caused by crystal formation.
  • a fentanyl content of 1 to 6% a high blood level can be attained when the drug is transdermally administered.
  • the fentanyl content is more preferably 1 to 4%, and further more preferably 2 to 4%, based on the whole mass of the drug layer.
  • the polyisobutylene comprises a high molecular weight polyisobutylene and a low molecular weight polyisobutylene.
  • the viscosity average molecular weight (Staudinger) of the high molecular weight polyisobutylene is preferably 800,000 to 1,600,000, more preferably 900,000 to 1,500,000, and further preferably 1,000,000 to 1,400,000.
  • the viscosity average molecular weight (Staudinger) of the low molecular weight polyisobutylene is preferably 30,000 to 80,000, more preferably 35,000 to 70,000, and further preferably 35,000 to 60,000.
  • the above average molecular weights are viscosity average molecular weights (Staudinger) measured in accordance with a viscosity method.
  • the mass ratio of the high molecular weight polyisobutylene to the low molecular weight polyisobutylene is preferably 1:9 to 2:3, and more preferably 1:7 to 1:3.
  • the polyisobutylene content in the drug layer is preferably 40 to 94%, more preferably 50 to 90%, and further preferably 60 to 85%, based on the whole mass of the drug layer.
  • a polyisobutylene content is below 40%, sufficient adhesion may not be achieved, whereas when a polyisobutylene content exceeds 94%, the cohesion of the pressure-sensitive adhesive and adhesive remnant may be caused.
  • the silicon-containing polymer contained in the drug layer refers to polymers containing silicon in the chemical skeleton. Preferred are, when mixed with the polyisobutylene, those not impairing the transdermal absorption of the drug, and even more preferred are those enhancing the transdermal absorption. Preferred examples of such silicon-containing polymers are those having an organopolysiloxane skeleton or compositions containing such a polymer. The latter compositions are more preferred.
  • a polymer having an organopolysiloxane skeleton has a hydroxyl groups (e.g., silanol group)
  • at least one of the hydroxyl groups is preferably capped by a trimethylsilyl group.
  • the above composition should be adhesive.
  • the capping by a trimethylsilyl group encompasses a form in which the terminal silanol group of the polymer having an organopolysiloxane skeleton is endcapped by a trimethylsilyl group.
  • polymers having an organopolysiloxane skeleton examples include polydimethylsiloxane (polymers indicated as MQ in accordance with ASTMD-1418), polymethylvinyl siloxane (polymers, indicated as VMQ in accordance with ASTMD-1418), polymethylphenyl siloxane (polymers indicated as PVMQ in accordance with ASTMD-1418).
  • compositions containing the polymer having an organopolysiloxane skeleton are those known as silicone pressure-sensitive adhesives.
  • examples of such a composition include those containing a silicone crude rubber, such as polydimethylsiloxane polymer, polymethylvinylsiloxane, polymethylphenylsiloxane, and an MQ resin (three dimensionally-structured silicone resins composed of an "M unit” such as (CH 3 ) 2 SiO 1/2 , and a "Q unit” such as SiO 2 ).
  • Usable compositions containing the polydimethylsiloxane polymer (and/or polymethylphenyl siloxane) and MQ resin are those into which a crosslinkage, such as 2SiCH 3 ⁇ Si-CH 2 -CH 2 -Si, is introduced using a crosslinking agent comprising an organic peroxide.
  • Usable compositions containing the polymethylvinyl siloxane and MQ resin are those in which hydrosilylization reaction undergoes using a crosslinking agent having an SiH group.
  • composition containing a polymer having an organopolysiloxane skeleton in which at least one of the hydroxyl groups is capped by a trimethylsilyl group examples include pressure sensitive adhesives produced by Dow Corning (BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4103, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4203, BIO-PSA 7-4301, BIO-PSA 7-4302, BIO-PSA7-4303).
  • Dow Corning BIO-PSA7-4102 a pressure sensitive adhesive, is particularly preferred.
  • Such a silicon-containing polymer may be used singly or two or more may be used by mixing.
  • the mass ratio of the polyisobutylene to silicon-containing polymer in the drug layer is 20:1 to 7:3.
  • the polyisobutylene and the silicon-containing polymer are provided in the form of containing a volatile ingredient such as organic solvents, the above mass ratio is calculated by deducting the volatile ingredient.
  • the silicon-containing polymer is a composition, the whole mass of the composition is used. With the mass ratio of the polyisobutylene to the silicon-containing polymer within the above range, a patch preparation sufficiently prevented from the sticking-out and crystal formation and having good drug permeability through the skin can be obtained.
  • the mass ratio of the polyisobutylene to the silicon-containing polymer in the drug layer is preferably 15:1 to 6:1, and more preferably 10:1 to 8:1.
  • the adhesive base used in the patch preparation of the present invention be substantially free of water.
  • substantially used herein means that the manufacturing process does not include the step in which water is intentionally added to the adhesive base. It does not exclude the moisture contained in raw materials or moisture such as sweat or the like absorbed by the pressure-sensitive adhesive while the patch preparation is applied to the skin.
  • the pressure-sensitive adhesive of the present invention may contain a transdermal absorption enhancer.
  • the transdermal absorption enhancer may be one or more compounds that exhibit the action of promoting transdermal absorption of the drug, and examples include fatty acids having a 6 to 20-carbon chain, aliphatic alcohols, fatty acid esters, alkyl ethers, aromatic organic acids, aromatic alcohols, aromatic organic esters, and aryl ethers.
  • lactate esters examples include lactate esters, acetate esters, monoterpene-based compounds, sesquiterpene-based compounds, Azone or derivatives thereof, glycerol fatty acid esters, sorbitan fatty acid esters, polysorbates, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oils, sucrose fatty acid esters.
  • transdermal absorption enhancer examples include caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alchohol, octyldodecanol, methyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate, ethyl acetate, propyl acetate, isopropyl palmitate, sorbitan monooleate, geraniol, thymol, eugenol, ter
  • the content of the transdermal absorption enhancer in the drug layer is preferably 0.01 to 20%, more preferably 0.1 to 15 mass%, and further preferably 0.5 to 10%, based on the whole mass of the drug layer.
  • the content of the transdermal absorption enhancer in the drug layer exceeds 20%, skin irritations such as redness, blisters, and/or the like may be caused.
  • the content is less than 0.01%, the benefit from the addition of the transdermal absorption enhancer may not be attained.
  • the patch preparation of the present invention may further contain, if necessary, a hydrophilic polymer to allow the patch preparation to absorb sweat and like fluids secreted from the skin.
  • a hydrophilic polymer include light anhydrous silicic acid, cellulose derivatives (carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC)), starch derivatives (pullulan), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyvinyl acetate (VA), carboxyvinyl polymer (CVP), ethylene-vinyl acetate copolymer (EVA), Eudragit, gelatin, polyacrylic acids, polyacrylic acid soda, polyisobutylene-maleic anhydride copolymer, alginic acid, sodium alginate, carragheenan, gum arabic, traga
  • the patch preparation of the present invention can contain, as necessary, antioxidants, filling agents, crosslinking agents, preservatives, melting point depressing agents, ultraviolet absorbers, and mineral oils.
  • antioxidants include tocopherol and ester derivatives thereof, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butyl hydroxyanisol.
  • the filling agent examples include talc, kaolin, water silica, light anhydrous silicic acid, aluminum hydroxide, calcium carbonate, magnesium carbonate, silicate (e.g., aluminum silicate, magnesium silicate), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide.
  • silicate e.g., aluminum silicate, magnesium silicate
  • silicic acid barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide.
  • crosslinking agent examples include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, unsaturated polyesters, etc. isocyanate compounds, block isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds.
  • Desirable examples of the preservative include disodium edetate, tetrasodium edetate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate.
  • Desirable melting point depressing agents are acetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, and salicylic acid.
  • the ultraviolet absorber are p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, cumarin derivatives, amino acid based compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives.
  • Preferred mineral oil is liquid paraffin.
  • antioxidants can be contained in a total proportion of preferably 30% or less, more preferably 20% or less, and particularly preferably 10% or less, based on the whole mass of the drug layer.
  • the patch preparation of the present invention can be manufactured by conventional methods such as solvent methods, hot melt method.
  • solvent methods hot melt method.
  • other ingredients are added to the organic solvent solution of the adhesive base to be contained, and the mixture is stirred, spread on the backing layer, and dried to form a drug layer, whereby the patch preparation of the present invention is obtained.
  • the adhesive base to be contained is applicable by a hot melt method, the adhesive base is dissolved at a high temperature, other ingredients are added thereto, the mixture is stirred and spread on the backing layer to form a drug layer, whereby the patch preparation of the present invention is obtained.
  • the patch preparation of the present invention can also be obtained by forming a drug layer using, in place of the backing layer, a release liner to be described later, and attaching a backing layer to the drug layer.
  • the patch preparation of the present invention is not limited in other layers or ingredients constituting the layers insofar as the patch preparation is provided with the drug layer comprising such a pressure-sensitive adhesive described above and a backing layer supporting the drug layer.
  • the patch preparation of the present invention can contain, in addition to a backing layer and a drug layer, a release liner provided on the drug layer.
  • the backing layer is not limited, and preferred usable examples include cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, aluminum sheets, or composite materials thereof.
  • the release liner is not limited as far as it has good release from the drug layer, and preferred usable examples include a polyethylene terephthalate (PET) film, polyethylene film, polypropylene film, polytetrafluoroethylene film.
  • PET polyethylene terephthalate
  • an active drug dosage can also be easily adjusted in accordance with symptoms, age, body weight, sex, etc., of a patient by cutting, or the like, the patch preparation.
  • the area of the drug layer to be contacted with the skin is not limited, but preferably 5 to 50 cm 2 , more preferably 5 to 30 cm 2 , and further preferably 5 to 10 cm 2 .
  • the patch preparation is conveniently handled when applied, whereas when the area is 5 cm 2 or more, sufficient skin permeability of the drug can be easily maintained.
  • a high molecular weight polyisobutylene (Vistanex MM L-100, product of Exxon Mobil) having a viscosity average molecular weight of 1,200,000 and a low molecular weight polyisobutylene (Oppanol B11, product of BASF) having a viscosity average molecular weight of 35,000 were dissolved in toluene, and a composition containing a polymer having an organopolysiloxane skeleton BIO-PSA•7-4102 (silicone pressure-sensitive adhesive) was added thereto to prepare an adhesive base solution.
  • An active drug comprising fentanyl and other ingredients comprising isopropyl myristate and oleyl alcohol were stirred at room temperature, the above adhesive base solution was added thereto, and the mixture was stirred to prepare a pressure-sensitive adhesive solution.
  • the thus obtained pressure-sensitive adhesive solution was applied to a polyethylene terephthalate (PET) film treated with fluorocarbon (release liner), and subsequently dried to form a drug layer having a thickness of 90 ⁇ m.
  • PET film i.e., a backing layer of 76.2 ⁇ m-thinckness, was attached onto the drug layer to obtain the patch preparation of the present invention.
  • the mass ratio of each ingredient is shown in Table 1.
  • the dorsal skin of a hairless mouse was extirpated and mounted, with the dermal side against a receptor layer side, on a flow-through cell in which warm water of 33°C was circulated around the outer part.
  • each patch preparation application area of the drug layer: 5 cm 2
  • each patch preparation was applied to the stratum corneum side of the skin, and sampling for the receptor solution was carried out at every one hour for 12 hours at a rate of 10 ml/hr using saline as the receptor layer, whereby the flow amount was measured, and the drug concentration was also measured by a high-performance liquid chromatography.
  • the drug permeation rate per hour was calculated from the measured values to determine the drug permeation rate per unit area of the skin at a steady state.
  • the skin permeation rates of the drug over time from the start of the test are shown in Table 1, and the maximum values of the skin permeation rate of the drug (maximum skin permeation rate) obtained during 12 hours are shown in Table 3.
  • Each patch preparation of Examples 1 to 3 and Comparative Examples 1 to 4 and 8 was packaged in a cellonium packaging material, and the package was sealed and stored at 25°C for 1 month to evaluate over-time stability (sticking-out: a part of a drug (base) protrudes from between a backing layer and base.
  • the results obtained are shown in Table 3.
  • the evaluation criteria for stability are shown below.
  • Each patch preparation of Examples 1 to 3 and Comparative Examples 1 to 4 and 8 are packaged in a cellonium packaging material, and the package was sealed and stored at 25°C for a month for visual inspection of the crystal formation. The results obtained are shown in Table 3. The evaluation criteria for crystal formation are shown below.

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Claims (9)

  1. Pflasterzubereitung, umfassend eine Trägerschicht und eine auf die Trägerschicht laminierte Arzneimittelschicht,
    wobei die Arzneimittelschicht aus einem Haftklebstoff besteht, der Polyisobutylen, ein siliciumhaltiges Polymer und wenigstens eine Verbindung, ausgewählt aus der Gruppe bestehend aus Fentanyl und pharmazeutisch verträglichen Salzen davon, umfasst, und
    ein Massenverhältnis des Polyisobutylens und des siliciumhaltigen Polymers in dem Haftklebstoff 20:1 bis 7:3 beträgt.
  2. Pflasterzubereitung gemäß Anspruch 1, wobei das Polyisobutylen ein Polyisobutylen mit hohem Molekulargewicht mit einem Viskositätsmittel des Molekulargewichts von 800.000 bis 1.600.000 und ein Polyisobutylen mit niedrigem Molekulargewicht mit einem Viskositätsmittel des Molekulargewichts von 30.000 bis 80.000 umfasst.
  3. Pflasterzubereitung gemäß Anspruch 1 oder 2, wobei das siliciumhaltige Polymer ein Polymer mit einem Organopolysiloxangerüst oder eine Zusammensetzung, die das Polymer enthält, ist.
  4. Pflasterzubereitung gemäß Anspruch 3, wobei das Polymer mit einem Organopolysiloxangerüst Hydroxylgruppen aufweist und wenigstens eine der Hydroxylgruppen durch eine Trimethylsilylgruppe verkappt ist.
  5. Pflasterzubereitung gemäß den Ansprüchen 3 oder 4, wobei das Organopolysiloxangerüst ein Polydimethylsiloxangerüst ist.
  6. Pflasterzubereitung gemäß einem der Ansprüche 3 bis 5, wobei die Zusammensetzung eine druckempfindliche Zusammensetzung ist.
  7. Pflasterzubereitung gemäß einem der Ansprüche 1 bis 6, wobei der Haftklebstoff außerdem einen Verstärker der transdermalen Absorption enthält.
  8. Pflasterzubereitung gemäß Anspruch 7, wobei der Verstärker der transdermalen Absorption wenigstens eine Verbindung, ausgewählt aus der Gruppe bestehend aus Isopropylmyristat, Isopropylpalmitat, Sorbitanmonooleat, Oleylalkohol, Propylenglycol, Dipropylenglycol und Octyldodecanol, ist.
  9. Pflasterzubereitung gemäß einem der Ansprüche 1 bis 8, wobei eine Fläche der Arzneimittelschicht, die mit der Haut in Berührung kommen soll, 5 bis 50 cm2 beträgt.
EP07767707.8A 2006-07-14 2007-06-27 Klebende zubereitung Active EP2042174B1 (de)

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JP2006194624 2006-07-14
PCT/JP2007/062906 WO2008007554A1 (fr) 2006-07-14 2007-06-27 Préparation d'adhésif

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EP2268244B1 (de) 2008-03-31 2018-07-04 Nitto Denko Corporation Durchdringendes abgabesystem und anwendungsverfahren dafür
JPWO2009139213A1 (ja) * 2008-05-15 2011-09-15 日本臓器製薬株式会社 プロクロルペラジン含有外用医薬組成物
EP2295046B1 (de) * 2009-09-14 2012-12-19 Acino AG Transdermales therapeutisches System zur Verabreichung von Fentanyl oder einem Analogstoff davon
WO2012105620A1 (ja) * 2011-02-02 2012-08-09 日東電工株式会社 貼付剤および貼付製剤
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US20090246263A1 (en) 2009-10-01
CN101454007B (zh) 2011-04-13
EP2042174A4 (de) 2012-10-10
ES2657887T3 (es) 2018-03-07
CN101454007A (zh) 2009-06-10
TW200812652A (en) 2008-03-16
JP5064391B2 (ja) 2012-10-31
CA2657592A1 (en) 2008-01-17
EP2042174A1 (de) 2009-04-01
KR101486599B1 (ko) 2015-01-26
JPWO2008007554A1 (ja) 2009-12-10
CA2657592C (en) 2014-10-21
WO2008007554A1 (fr) 2008-01-17
US8647664B2 (en) 2014-02-11
KR20090029790A (ko) 2009-03-23
TWI462755B (zh) 2014-12-01

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